Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders

Abstract

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS celltype eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders..

Inter-individual variation in human cortical cell type abundance and expression

“…This result indicates neuronal cell type-agnostic genetic control of LRRC37A2 which should recapitulate previous bulk RNA-seq eQTL studies. Together, these results show that genetic control of gene expression can extend to finer cell type resolutions than previously studied (25)(26)(27)(62)(63)(64) and may be increasingly relevant for diseases including neurodegenerative disorders that may selectively affect specific cell types (20).…”

“…Second, sampling neurosurgical tissues permits comparison of different underlying medical conditions between donors but introduces challenges in direct comparisons with similar studies using postmortem tissue and might result in biases due to tissue shape and sampling of variable cortical regions across donors. Third, the sample size is relatively small, although comparable results were found in a similar study in aging brain (27). Finally, the total number of cells collected per donor was relatively low (~4000 on average, collected from a single tissue section) limiting analyses possible for rare types.…”

“…We report subclass-specific eQTLs providing an opportunity to associate disease-risk genes and variants from GWAS ( 69 ) with preferential regulation of expression in individuals or sets of subclasses. Current eQTL studies have used coarser groupings of cells than in this study and found eQTLs specific to excitatory and GABAergic neurons ( 27 ) that we can further resolved into subclass-level eQTLs to hone in more granular cell types targeted by variants associated with neurological disease. Furthermore, computational deconvolution ( 14 , 15 ) of eQTL analyses performed on bulk tissue ( 26 , 62 , 73 ) to resolve cell type signals can be refined using ( 14 , 15 , 26 ) the subclass-specific eQTLs reported in this study.…”

“…We next aimed to extend previous studies linking genetic variants to variation in gene expression (24)(25)(26)(27)(62)(63)(64) by identifying cell type-specific eQTLs from the combined single cell RNA-seq and high-quality whole genome sequencing (Fig. S10) performed for each individual in our study.…”

“…Combined genotype and snRNA-seq data in even small cohorts permit investigation of the functional effects of disease-associated variants and identification of genes whose expression is under genetic control through expression quantitative trait locus (eQTL) analysis. Existing studies that perform eQTL analysis using bulk RNA-seq or snRNA-seq provide insights into brain-specific eQTLs ( 24 , 25 ), some of which are associated with diseases like Alzheimer’s disease ( 20 , 26 , 27 ). However, the current resolution of cell type-specific eQTL analysis is limited to the broadest cell types and the extent to which genetic variants can modulate expression within finer cell type annotation remains unexplored.…”